Use of pyrimidine derivatives for the prevention of cancer, on their own or in combination with other therapeutic measures

ABSTRACT

Use of pyrimidine derivatives for the prevention of cancer, on their own or in combination with other therapeutic measures. 
     The present invention is concerned with the use of pyrimidine derivatives as agents for the prevention of carcinomatous disorders. 
     The pyrimidine derivatives used are active compounds of the formula I ##STR1## in which R 1  to R 7  have the meaning indicated, and their physiologically tolerable salts.

DESCRIPTION

Use of pyrimidine derivatives for the prevention of cancer, on their ownor in combination with other therapeutic measures

The present invention is concerned with the use of pyrimidinederivatives as agents for the prevention of carcinomatous disorders.

The pyrimidine derivatives used are active compounds of the formula I##STR2## in which R¹ is hydrogen, halogen, cyano, nitro,trifluoromethyl, amino, (C₁ -C₆)-alkyl, (C₁ -C₆)-hydroxyalkyl, (C₁-C₆)-alkoxy, (C₆ -C₁₂)-aryl, (C₁ C₆)-alkoxycarbonyl-(C₁ -C₆)-alkyl, (C₁-C₆)-alkyl-S--(C₁ -C₆)-alkyl, (C₁ -C₆)-alkyl-SO-(C₁ -C₆)-alkyl, (C₁-C₆)-alkyl-SO₂ --(C₁ -C₆)-alkyl, dihydroxy-(C₁ -C₆)-alkyl, aryl,heteroaryl, heteroaryl-(C₁ -C₆)-alkyl, aryl-(C₁ -C₆)-alkyl, (C₁-C₆)-alkoxycarbonylaryl, aryl-(C₁ -C₆)-alkyloxy or heteroaryl-(C₁-C₆)-alkyloxy,

heteroaryl is pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl;

where aryl and heteroaryl independently of one another can besubstituted by one or more substituents selected from the groupconsisting of chlorine, bromine, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy,--S--(C₁ -C₆)-alkyl, --SO--(C₁ -C₆)-alkyl,--SO₂ --(C₁ -C₆)-alkyl,hydroxy-(C₁ -C₆)-alkyl, trifluoromethyl, or ##STR3## W, Q, Zindependently of one another are H, (C₁ -C₆)-alkyl, trifluoromethyl,phenyl, furyl, triazolyl, thiazolyl, thienyl, where phenyl, furyl,triazolyl, thiazolyl, thienyl independently of one another can be mono-to trisubstituted by (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, trifluoromethyl,hydroxyl, or

R¹ is --(C═O)--R⁶

R⁶ is H, (C₁ -₆)-alkyl, aryl, heteroaryl

heteroaryl is pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl; where aryland heteroaryl independently of one another can be substituted by one tothree substituents selected from the group consisting of chlorine,bromine, nitro, trifluoromethyl, (C₁ -₆)-alkoxy, --S--(C₁ -C₆)-alkyl,--SO--(C₁ -C₆)-alkyl, --SO₂ --(C₁ -C₆)-alkyl, or ##STR4## R⁷ is aryl,heteroaryl heteroaryl is pyridyl, furyl, thienyl, imidazolyl, pyrazolyl,triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl,benzothienyl, quinolyl, where aryl and heteroaryl independently of oneanother can be substituted by one to three substituents selected fromthe group consisting of chlorine, bromine, nitro, trifluoromethyl, (C₁-C₆)-alkyl, (C₁ -C₆)-alkoxy, --S--(C₁ -C₆)-alkyl, --SO--(C₁ -C₆)-alkyl,--SO₂ --(C₁ -₆)-alkyl;

Y hydrogen, benzyl, acetyl, benzoyl, phenyl, naphthyl, furyl, thienyl,thiazolyl, oxazolyl, where the cycles or heterocycles can be substitutedby one or two substituents selected from the group consisting ofchlorine, bromine, nitro, trifluoromethyl, (C₁ -₆)-alkyl, (C₁-C₆)-alkoxy, --S--(C₁ -C₆)-alkyl, --SO--(C₁ -C₆)-alkyl, --SO₂ --(C₁-₆)-Alkyl;

R², R³ independently of one another are hydrogen, (C₁ -C₆)-alkyl, (C₆-C₁₂)-aryl, (C₆ -C₁₂)-arylalkyl having 1-4 alkyl carbon atoms, wherearyl can be substituted by one to three substituents selected from thegroup consisting of chlorine, bromine, trifluoromethyl, (C₁ -C₆)-alkyl,(C₁ -C₆)-alkoxy, or

R² and R³, together with the nitrogen to which they are bonded, form theazetidino, pyrrolidino, piperidino, piperazino or morpholino group,where the heterocycles can be substituted by one or two substituentsselected from the group consisting of chlorine, bromine,trifluoromethyl, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, --S--(C₁ -C₆)-alkyl,--SO--(C₁ -₆)-alkyl, --SO₂ --(C₁ -C₆)-alkyl, sulfamoyl, N--(C₁-C₄)-alkylsulfamoyl, N,N--(C₁ -C₄)-dialkylsulfamoyl, (C₁-₆)-alkoxycarbonyl, N,N--(C₁ -C₄)-dialkylcarbamoyl, N--(C₁-C₄)-alkylcarbamoyl, N--(C₆ -C₁₂)-arylcarbamoyl, (C₆ -C₁₂)-arylcarbamoylsubstituted in the aryl radical by (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy,halogen, NO₂, NH₂, CN or CF₃, (C₆ -C₁₂)-arylcarbonyl substituted in thearyl radical by (C₁ -C₄)-alkoxy, halogen, NO₂, NH₂, CN or CF₃, (C₁-C₆)-alkylsulfonyl, (C₁ -C₆)-alkylsulfinyl, (C₆ -C₁₂)-arylsulfonyl, (C₆-C₁₂)-arylsulfonyl substituted in the aryl radical by (C₁ -₄)-alkyl, (C₁-C₄)-alkoxy, halogen, NO₂, NH₂, CN or CF₃, heteroarylcarbonyl orheteroarylsulfonyl;

R⁴ and R⁵ independently of one another are hydrogen, halogen, cyano,nitro, trifluoromethyl, amino, (C₁ -C₆)-alkyl, (C₁ -₆)-hydroxyalkyl, (C₁-C₆)-alkoxy, (C₆ -C₁₂)-aryl, naphthyl, furyl, where (C₆ -C₁₂)-aryl,naphthyl and furyl can be substituted by one or two substituentsselected from the group consisting of chlorine, bromine,trifluoromethyl, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, --S--(C₁ -C₆)-alkyl,--SO--(C₁ -C₆)-alkyl, --SO₂ --(C₁ -₆)-alkyl, hydroxyl; and theirphysiologically tolerable salts.

Preferred compounds of the formula I are those in which

R¹ is cyano, trifluoromethyl, (C₁ -C₆)-alkyl, (C₁ -C₆)-hydroxyalkyl, (C₁-C₆)-alkoxy or (C₆ -C₁₂)-aryl;

R⁴ and R⁵ are hydrogen, halogen or trifluoromethyl;

R², R³ independently of one another are hydrogen, (C₁ -C₆)-alkyl, (C₆-C₁₂)-aryl or (C₆ -C₁₂)-arylalkyl having 1-4 alkyl carbon atoms, or

R² and R³, together with the nitrogen to which they are bonded, form theazetidino, pyrrolidino, piperidino, piperazino or morpholino group, oran azetidino, pyrrolidino, piperidino, piperazino or morpholino groupsubstituted by identical or different groups R⁶ and R⁷ ;

R⁶, R⁷ are (C₁ -C₆)-alkyl, sulfamoyl, N--(C₁ -C₄)-alkylsulfamoyl,N,N--(C₁ -C₄)-dialkylsulfamoyl, (C₁ -C₆)-alkoxycarbonyl, N,N--(C₁-C₄)-dialkylcarbamoyl, N--(C₁ -C₄)-alkylcarbamoyl, N--(C₆-C₁₂)-arylcarbamoyl, (C₆ -C₁₂)-arylcarbamoyl substituted in the arylradical by (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, halogen, NO₂, NH₂, CN orCF₃, carbamoyl, (C₁ -C₆)-alkylcarbonyl, (C₆ -C₁₂)-arylcarbonyl, (C₆-C₁₂)-arylcarbonyl substituted in the aryl radical by (C₁ -₄)-alkyl, (C₁-C₄)-alkoxy, halogen, NO₂, NH₂, CN or CF₃, (C₁ -C₆)-alkylsulfonyl, (C₁-C₆)-alkylsulfinyl, (C₆ -C₁₂)-arylsulfonyl, (C₆ -C₁₂)-arylsulfonylsubstituted in the aryl radical by (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy,halogen, NO₂, NH₂, CN or CF₃, heteroarylcarbonyl or heteroarylsulfonylor one of the substituents R⁶, R⁷ is hydrogen, and their physiologicallytolerable salts.

Particularly preferred compounds of the formula I are those in which

R¹ is --CH₂ --OH, --CH₃,

R⁴, R⁵ are hydrogen,

R², R³, together with the nitrogen to which they are bonded, are apiperazino group, where this piperazino group is substituted in the4-position by an N,N-dimethylaminosulfonyl group.

U.S. Pat. No. 5,138,058, WO 94107867, and the scientific literature[e.g. K. Geisen, R. Utz, H. Grotsch, H. J. Lang and H. Nimmesgern,Arzneimittel-Forsch./Drug Res. 44 (II) (1994): 1032-1043] describe alarge number of pharmacological actions for the compounds of the formulaI. The disclosures of these three documents are specificallyincorporated by reference herein. Thus, for example, by treatment ofdiabetic animals with the pyrimidine derivatives of the formula I asignificant improvement in the nerve conduction velocity is achieved.Additionally, in the treatment of diabetic rats with the pyrimidinesmentioned, a normalization of the glomerular filtration rate and adecrease in albuminuria is observed. The effects described in theliterature make the compounds useful pharmaceuticals for the prophylaxisand treatment of disorders of the diabetic type, in particular for theprophylaxis and treatment of late diabetic damage.

It has now surprisingly been found that the pyrimidine derivatives ofthe formula I described in the literature mentioned and the patentsindicated are able to decrease or to inhibit completely the developmentof tumors. Thus the compounds mentioned are already able on their ownand without addition of other substances to bring about a favorabletherapeutic inhibition, in particular of tumor formation.

The present invention also relates to pharmaceutical preparations which,beside nontoxic, inert pharmaceutically suitable excipients, contain oneor more active compounds according to the invention or which consist ofone or more active compounds according to the invention, and toprocesses for the production of these preparations.

Nontoxic inert pharmaceutically suitable excipients are understood asmeaning pharmaceutically acceptable solid, semisolid or liquid diluents,fillers and formulation auxiliaries of any type, which after mixing withthe active compound bring this into a form suitable for administration.

Suitable administration forms of the compounds according to theinvention are, for example, tablets, coated tablets, capsules, pills,aqueous solutions, suspensions and emulsions, if appropriate sterileinjectable solutions, nonaqueous emulsions, suspensions and solutions,sprays and also preparation forms with protracted release of activecompound.

The therapeutically active compounds should be present in theabovementioned pharmaceutical preparations expediently in aconcentration of approximately 0.1 to 99.0, preferably of 0.5 to 70.0,percent by weight of the total mixture.

The administration concentrations for solutions and aerosols in the formof spray is in general 0.1 to 20, preferably 0.5-5, percent by weight.

The abovementioned pharmaceutical preparations can also contain furtherpharmaceutical active compounds in addition to the active compoundsaccording to the invention.

The abovementioned pharmaceutical preparations are prepared in acustomary manner according to known methods, e.g. by mixing the activecompound(s) with the excipient(s).

The active compounds or the pharmaceutical preparations can beadministered orally, parenterally, intraperitoneally and/or rectally.

The compounds of the present invention and their salts can be used forthe production of pharmaceutical preparations which contain an effectiveamount of the active substance together with excipients and which aresuitable for enteral and parenteral administration. Tablets or capsules(gelatin capsules) are preferably used which contain the active compoundtogether with diluents or excipients, e.g. lactose, dextrose, canesugar, mannitol, sorbitol, cellulose, various types of starch and/orglycerol, and lubricants such as silica, talc, stearic acid or itssalts, such as magnesium or calcium stearate, and/or polyethyleneglycol. Tablets also contain binders such as magnesium carbonate,magnesium aluminum silicate, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone and, if required, colorants, flavorings andsweeteners. Injectable solutions are preferably isotonic aqueoussolutions or suspensions, which can be sterilized and can containauxiliaries, such as preservatives, stabilizers, wetting agents and/oremulsifiers, solubilizers, salts for regulating the osmotic pressureand/or buffer substances. The pharmaceutical preparations according tothe invention, which if desired can contain further pharmacologicallyactive substances, are prepared, for example, by means of conventionalmixing, granulating and pan-coating processes, and contain 0.1% topreferably 80%, preferably approximately 5% to approximately 65%, of theactive compound.

Oral administration takes place in pharmaceutically customarypreparations, for example in the form of tablets, coated tablets orcapsules, which, for example, per daily dose contain 5 to 1000 mg,preferably 20 to 200 mg, of the active compound as a mixture with acustomary excipient and/or constituent, it being possible to giveindividual doses of 5 to 200 mg, preferably once to three times daily.

It may, however, be necessary to deviate from the doses mentioned,namely depending on the nature and the body weight of the subject to betreated, the nature and severity of the disease, the type of preparationand of administration of the pharmaceutical, and the time or intervalwithin which administration takes place. Thus in some cases it may beadequate to manage with less than the abovementioned amount of activecompound, while in other cases the abovementioned amount of activecompound has to be exceeded. The setting of the optimum dose and type ofadministration of the active compounds necessary in each case can easilybe carried out by any person skilled in the art on the basis of hisexpert knowledge.

Experimental demonstration of the antitumor action Thetumor-prophylactic action of the pyrimidine derivatives of the formula Iwas tested on rats which had been pretreated with streptozotocin.Streptozotocin is a methylnitrosourea derivative having alkylatingproperties. It is an oncogenic and cytotoxic substance which waslicensed by the US Food and Drug Administration for the treatment ofmetastatic islet carcinoma of the pancreas. In rats, a singleintravenous bolus injection of streptozotocin leads to the acuteoccurrence of diabetes mellitus and over a longer period of time to theformation of adenomas and adenocarcinomas of the kidney (Lit of Dr.Geisen VII-XII). In this model of streptozotocin-treated rats, chronictreatment with the pyrimidine derivatives according to the inventionleads to the almost complete abolition of the development of renaltumors, whereas 80% of the untreated animals show the formation ofadenocarcinomas in the kidneys.

EXPERIMENTAL EXAMPLE

24 male rats having a body weight of 210-230 g were administered 60mg/kg of streptozotocin sulfate intravenously for tumor induction. Sixweeks after administration of streptozotocin, 12 of the 24 diabeticanimals received a dose of 50 mg/kg of2-methyl4-(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimidine orallysupplied daily with the drinking water.

After 288 days of treatment, the experiment was ended, 3 animals of thecontrol group and 2 animals of the group treated with2-methyl-4-(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimidine dyingprematurely. The kidney weight of the control animals was significantlyhigher than the kidney weight of the animals which received2-methyl-4-(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimidine. Onlyone of ten of the animals treated with2-methyl-4-(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimidine haddeveloped a tumor of the size of a lentil in a kidney. In contrast, 7 ofthe 9 control animals developed pea- to bean-size tumors.

According to the invention, the use of a pyrimidine derivative of theformula I is therefore suitable for the production of a pharmaceuticalfor the inhibition of tumor growth and for the prevention oftumorigenesis.

The use of a pyrimidine derivative of the formula I for the productionof a pharmaceutical for the prevention of oncoses in combination with atherapeutic used in cancer prevention and cancer treatment is preferred.

The use of a pyrimidine derivative of the formula I for the productionof a pharmaceutical for the prevention of oncoses in combination with aphysical, tumor-therapeutic measure, in particular radiation therapy orhyperthermia therapy, is further preferred.

The use of a pyrimidine derivative of the formula I for the productionof a pharmaceutical for the prevention of oncoses in combination with animmunomodulator is likewise preferred.

The use of a pyrimidine derivative of the formula I for the productionof a pharmaceutical for the prevention of oncoses in combination with aninhibitor of the cellular sodium-hydrogen exchanger is furthermorepreferred.

The use of a pyrimidine derivative of the formula I in combination withother substances which potentiate the action of the pyrimidinederivatives, without themselves having an action directed against tumorformation and tumor growth, for the production of a pharmaceutical forthe prevention of oncoses is particularly preferred.

The use of a pyrimidine derivative of the formula I for the productionof a pharmaceutical for the prevention of oncoses in combination withpharmacologically tolerable acids or acid-producing nutritive measuresis furthermore preferred.

The use of a pyrimidine derivative of the formula I for the productionof a pharmaceutical for the prevention of oncoses in combination withmodulators of biological pH regulation is furthermore preferred.

The use of a pyrimidine derivative of the formula I for the productionof a pharmaceutical for the prevention of oncoses in combination withinhibitors of carboanhydratase is furthermore preferred.

The use of a pyrimidine derivative of the formula I for the productionof a pharmaceutical for the prevention of oncoses in combination with aninhibitor of the chloride-bicarbonate exchanger is furthermorepreferred.

The use of2-methyl4-(4-N,N-dimethylaminosulfonyl-1-piperazino)-pyrimidine and of2-hydroxymethyl4-(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimidine asa pyrimidine component of a tumor therapeutic is very particularlypreferred.

Even on their own without addition of other substances, the pyrimidinederivatives bring about a favorable therapeutic inhibition of tumorgrowth or of tumor formation.

The relatively low toxic potential of the pyrimidines described here canbe combined advantageously with other forms of treatment possible incancer treatment, and in many cases more toxic, such as, for example,

with chemotherapeutic measures,

with irradiation measures,

with immunomodulators,

with a hyperthermia treatment,

with inhibitors of the cellular sodium-proton exchanger, such as, forexample, with amiloride or HOE 642,

with substances which have an inhibitory action on carboanhydratase,

with parallel administration of therapeutically nontoxic and tolerableacids or acid-producing nutritive treatment (such as, for example, theadministration of relatively large amounts of glucose/sucrose, e.g. inthe form of cola).

The advantage of such a combined treatment can be that the customarymore toxic principles of treatment at present (irradiation,chemotherapy, hyperthermia) can be made milder and decreased and/or theantitumor action of a pyrimidine derivative according to the inventioncan be potentiated.

What is claimed is:
 1. A method for the prevention of a carcinomatousdisorder, which comprises administering to a host in need of saidprevention an effective amount of at least one compound of formula I##STR5## or a physiologically tolerable salt thereof, in whichR¹ ishydrogen, halogen, cyano, nitro, trifluoromethyl, amino, (C₁ -C₆)-alkyl,(C₁ -C₆)-hydroxyalkyl, (C₁ -C₆)-alkoxy, (C₆ -C₁₂)-aryl, (C₁-C₆)-alkoxycarbonyl-(C₁ -C₆)-alkyl, (C₁ -C₆)-alkyl--S--(C₁ -C₆)-alkyl,(C₁ -C₆)-alkyl-SO--(C₁ -C₆)-alkyl, (C₁ -C₆)-alkyl--SO₂ --(C₁ -C₆)-alkyl,dihydroxy-(C₁ -C₆)-alkyl, aryl, heteroaryl, heteroaryl-(C₁ -C₆)-alkyl,aryl-(C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxycarbonylaryl, aryl-(C₁ -C₆)-alkyloxyor heteroaryl-(C₁ -C₆)-alkyloxy,wherein heteroaryl is pyridyl, furyl,tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl,oxazolyl, or benzothiazolyl; where aryl and heteroaryl independently ofone another can be unsubstituted or substituted by one or moresubstituents selected from chlorine, bromine, (C₁ -C₆)-alkyl, (C₁-C₆)-alkoxy, --S--(C₁ -C₆)-alkyl, --SO--(C₁ -C₆)-alkyl, --SO₂ --(C₁-C₆)-alkyl, hydroxy-(C₁ -C₆)-alkyl, and trifluoromethyl, or ##STR6## inwhich the dashed line is an optional bond; W, Q, Z independently of oneanother are H, (C₁ -C₆)-alkyl, trifluoromethyl, phenyl, furyl,triazolyl, thiazolyl, or thienyl, where phenyl, furyl, triazolyl,thiazolyl, thienyl independently of one another can be mono- totrisubstituted by (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, trifluoromethyl, orhydroxyl, or R¹ is --(C═O)--R⁶ R⁶ is H, (C₁ -C₆)-alkyl, aryl, orheteroarylwherein heteroaryl is pyridyl, furyl, tetrahydrofuryl,thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, orbenzothiazolyl; where aryl and heteroaryl independently of one anothercan be unsubstituted or substituted by one to three substituentsselected from chlorine, bromine, nitro, trifluoromethyl, (C₁-C₆)-alkoxy, --S--(C₁ -C₆)-alkyl, --SO--(C₁ -C₆)-alkyl, and --SO₂ --(C₁-C₆)-alkyl, or ##STR7## R⁷ is aryl or heteroaryl wherein heteroaryl ispyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl,oxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, or quinoyl, wherearyl and heteroaryl independently of one another can be unsubstituted orsubstituted by one to three substituents selected from chlorine,bromine, nitro, trifluoromethyl, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy,--S--(C₁ -C₆)-alkyl, --SO--(C₁ -₆)-alkyl, and --SO₂ --(C₁ -C₆)-alkyl;R², R³ independently of one another are hydrogen, (C₁ -₆)-alkyl, (C₆-C₁₂)-aryl, or (C₆ -C₁₂)-arylalkyl having 1-4 alkyl carbon atoms, wherearyl can be unsubstituted or substituted by one to three substituentsselected from chlorine, bromine, trifluoromethyl, (C₁ -C₆)-alkyl, and(C₁ -C₆)-alkoxy, or R² and R³, together with the nitrogen to which theyare bonded, form the azetidino, pyrrolidino, piperidino, piperazino ormorpholino group, where the heterocycles can be unsubstituted orsubstituted by one or two substituents selected from chlorine, bromine,trifluoromethyl, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, --S--(C₁ -C₆)-alkyl,--SO--(C₁ -C₆)-alkyl, --SO₂ --(C₁ -C₆)-alkyl, sulfamoyl, N--(C₁-C₄)-alkylsulfamoyl, N,N--(C₁ -C₄)-dialkylsulfamoyl, (C₁-C₆)-alkoxycarbonyl, N,N--(C₁ -C₄)-dialkylcarbamoyl, N--(C₁-C₄)-alkylcarbamoyl, N--(C₆ -C₁₂)-arylcarbamoyl, (C₆ -C₁₂)-arylcarbonylsubstituted in the aryl radical by (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy,halogen, NO₂, NH₂, CN or CF₃, (C₆ -C₁₂)-arylcarbonyl substituted in thearyl radical by (C₁ -C₄)-alkoxy, halogen, NO₂, NH₂, CN or CF₃, (C₁-C₆)-alkylsulfonyl, (C₁ -C₆)-alkylsulfinyl, (C₆ -C₁₂)-arylsulfonyl, (C₆-C₁₂)-arylsulfonyl substituted in the aryl radical by (C₁ -C₄)-alkyl,(C₁ -C₄)-alkoxy, halogen, NO₂, NH₂, CN or CF₃, heteroarylcarbonyl orheteroarylsulfonyl; R⁴ and R⁵ independently of one another are hydrogen,halogen, cyano, nitro, trifluoromethyl, amino, (C₁ -C₆)-alkyl, (C₁-C₆)-hydroxyalkyl, (C₁ -C₆)-alkoxy, (C₆ -C₁₂)-aryl, naphthyl, or furyl,where (C₆ -C₁₂)-aryl, naphthyl and furyl can be unsubstituted orsubstituted by one or two substituents selected from chlorine, bromine,trifluoromethyl, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, --S--(C₁ -C₆)-alkyl,--SO--(C₁ -C₆)-alkyl, --SO₂ --(C₁ -C₆)-alkyl, and hydroxyl.
 2. A methodas claimed in claim 1, wherein the radicals R¹ to R⁷ have the followingmeaningR¹ is cyano, trifluoromethyl, (C₁ -C₆)-alkyl, (C₁-C₆)-hydroxyalkyl, (C₁ -C₆)-alkoxy or (C₆ -C₁₂)-aryl; R⁴ and R⁵independently of one another are hydrogen, halogen or trifluoromethyl;R², R³ independently of one another are hydrogen, (C₁ -C₆)-alkyl, (C₆-C₁₂)-aryl or (C₆ -C₁₂)-arylalkyl having 1-4 alkyl carbon atoms, or R²and R³, together with the nitrogen to which they are bonded, form theazetidino, pyrrolidino, piperidino, piperazino or morpholino group, oran azetidino, pyrrolidino, piperidino, piperazino or morpholino groupsubstituted by identical or different groups R⁶ and R⁷ ; R⁶, R⁷ are (C₁-C₆)-alkyl, sulfamoyl, N--(C₁ -C₄)-alkylsulfamoyl, N,N--(C₁-C₄)-dialkylsulfamoyl, (C₁ -C₆)-alkoxycarbonyl, N,N--(C₁-C₄)-dialkylcarbamoyl, N--(C₁ -C₄)-alkylcarbamoyl, N--(C₆-C₁₂)-arylcarbamoyl, (C₆ -C₁₂)-arylcarbamoyl substituted in the arylradical by (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, halogen, NO₂, NH₂, CN orCF₃, carbamoyl, (C₁ -C₆)-alkylcarbonyl, (C₆ -C₁₂)-arylcarbonyl, (C₆-C₁₂)-arylcarbonyl substituted in the aryl radical by (C₁ -C₄)-alkyl,(C₁ -C₄)-alkoxy, halogen, NO₂, NH₂, CN or CF₃, (C₁ -C₆)-alkylsulfonyl,(C₁ -C₆)-alkylsulfinyl, (C₆ -C₁₂)-arylsulfonyl, (C₆ -C₁₂)-arylsulfonyl,substituted in the aryl radical by (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy,halogen, NO₂, NH₂, CN or CF₃, heteroarylcarbonyl or heteroarylsulfonylor one of the substituents R⁶, R⁷ is hydrogen.
 3. A method as claimed inclaim 1, wherein the radicals R¹ to R⁷ have the following meaningR¹ is--CH₂ --OH, or --CH₃, R⁴, R⁵ are hydrogen, R², R³, together with thenitrogen to which they are bonded, are a piperazino group, where thispiperazino group is substituted in the 4-position by anN,N-dimethylaminosulfonyl group.
 4. A method of claim 1, wherein thecompound of the formula I is2-methyl-4-(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimidine or2-hydroxymethyl-4-(4-N,N-dimethylamino-sulfonyl-1-piperazino)pyrimidine.5. A method as claimed in claim 1, wherein the carcinomatous disorder isa tumor.